Species differences in susceptibility of transplanted and cultured pancreatic islets to the beta-cell toxin alloxan

The beta -cell toxin alloxan, which produces oxygen radicals, is a model su bstance in studies of type 1 diabetes. Recently, human beta -cells have bee n found to be relatively resistant to this toxin. To clarify species differ ences in alloxan diabetogenicity, and oxygen radical toxicity, mouse, rat, rabbit, dog, pig, human and guinea pig islets have been studied after allox an exposure. Using a standardized in vivo model, where islets were transpla nted to nude mice, the different islets were compared. The results demonstr ated that mouse and rat islet grafts were morphologically disturbed by allo xan and ROS. Rabbit and dog islet graft morphology was reasonably intact; a nd human, porcine, and guinea pig islet grafts were all well preserved. Fur thermore, ultrastructural signs of apoptosis and necrosis, disturbances in the insulin secretory pattern during and after an alloxan perifusion, and i slet lysosomal enzyme activities were studied in vitro in islets from some species. Guinea pig beta -cells were affected by alloxan, but a regeneratio n process compensated for the observed apoptotic and necrotic cell death. H uman islets did not show any signs of alloxan-induced damage in the differe nt models studied. Finally, no correlation between high alloxan sensitivity and high lysosomal enzyme activity was found. Thus, the beta -cell lysosom es are hardly specific targets for alloxan. (C) 2001 Academic Press.